Study protocol for a phase III randomised controlled trial of Sailuotong (SLT) for vascular dementia and Alzheimer’s disease with cerebrovascular disease

Vascular dementia (VaD) accounts for 15–20% of all dementia cases. It is a syndrome of acquired cognitive impairment with a complex pathophysiological basis. A novel herbal formulation (Sailuotong; SLT) consisting of Panax ginseng C.A Mey, Ginkgo biloba L and Crocus sativus L extracts was developed to treat VaD. Preclinical animal studies found significant improvements in memory and in pathogenic biochemical parameters. Appropriate safety of SLT was shown in acute and chronic toxicity studies, and early clinical trials of SLT demonstrated enhancements in cognition in VaD patients. A fully powered study with a long intervention period is needed to confirm the efficacy and safety of this novel intervention. A rigorous phase III clinical trial was developed with the aim of recruiting 238 patients diagnosed with mild to moderate probable VaD, or VaD mixed with Alzheimer’s disease (where cerebrovascular disease is the clinical dominant contributor to dementia, abbreviated as CVD+AD). Using a permuted block strategy, participants will be randomly allocated to receive SLT (120 mg bd) or placebo capsules for an intervention period of 52 weeks and will be followed-up for an additional 13 weeks. The primary outcome measures are the Vascular Dementia Assessment Scale-cognitive subscale and Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale. Secondary outcome measures include the Clinician’s Interview Based Impression of Change-Plus, CLOX, EXIT-25, Neuropsychiatric Inventory-Clinician rating scale, and Dementia Quality of Life questionnaire. Safety is assessed through adverse event reports and liver, renal, and coagulation studies. Primary and secondary outcome measures will be compared between treatment and placebo groups, using intention to treat and per protocol analyses. We hypothesise that a 52-week treatment of SLT will be clinically effective and well tolerated in participants with VaD or AD+CVD. This project will provide vital efficacy and safety data for this novel treatment approach to VaD.

I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to protect the best interests of the study participants.
I agree to conduct and supervise this investigation and to ensure that all associates, colleagues, and employees assisting in the conduct of this study are informed about their obligations in meeting these commitments.
I will conduct the study in accordance with Good Clinical Practice, the Declaration of Helsinki, and the moral, ethical and scientific principles that justify medical research. The study will be conducted in accordance with all relevant laws and regulations relating to clinical studies and the protection of patients.
I will ensure that the requirements relating to Human Research Ethics Committee (HREC) review and approval are met. I will provide Australia Shineway Technology Pty Ltd with any material which is provided to the HREC for Ethical approval.
I agree to maintain adequate and accurate records and to make those records available for audit and inspection in accordance with relevant regulatory requirements.
I agree to promptly report to the HREC any changes in the research activity and all unanticipated problems involving risks to human participants or others.   This project is innovative and will provide vital efficacy and safety data for this novel standardised formulation. Success in this project may lead to a breakthrough intervention for VaD. The project will help build complementary medicine research capacity through national and international collaborations.

Objectives
In this multicentre, randomised, double-blind, placebo controlled trial, we propose to evaluate the clinical effectiveness of SLT for the symptomatic improvement of VaD in 238 patients with mild to moderate probable VaD or Alzheimer's disease with cerebrovascular disease (AD+CVD). Specifically, the objectives of the study are to: • determine the efficacy of the herbal intervention on cognitive function, activities of daily living, and quality of life, and • monitor the safety of SLT as a treatment for VaD or AD+CVD during 52 weeks We hypothesise that a 52 week treatment of SLT as compared with placebo will be clinically effective and well tolerated in participants with VaD or AD+CVD. The design of this study follows the European Medicines Agency's Guidelines on Medicinal Products for the Treatment of Alzheimer's Disease and Other Dementia. 1

Efficacy Endpoints
Primary efficacy endpoints The primary efficacy endpoint will be the difference between SLT and the placebo groups in the changes in Vascular Dementia Assessment Scale-cognitive Subscale (VaDAS-cog) and Alzheimer's disease Cooperative Study-activities of daily living (ADCS-ADL) scores from Baseline and 26-, and 52-week follow-up visits.

Secondary efficacy endpoints
The secondary efficacy endpoints of the study will be the differences between the SLT and the placebo groups in the changes between baseline and 26-, and 52-week follow-up visits in: • Scores of Clinician's Interview Based Impression of Change-plus (CIBIC-plus) • Scores of additional executive function tests including CLOX and EXIT-25 from Safety endpoints • Number of Adverse events and serious adverse events will be monitored during the course of the study.
• Changes in liver, renal, coagulation will be monitored during the course of the study.

Vascular Dementia
Dementia is a leading cause of mental and physical disability in the elderly and carries the highest disability weighting of all illnesses. VaD is a clinical syndrome of acquired intellectual and functional impairment that results from cerebrovascular and cardiovascular diseases and is the second most common cause of dementia after Alzheimer's disease (AD), accounting for 15-20% of all cases in western countries. 2 The prevalence of VaD is between 1 and 4% in individuals over the age of 65 years. 3 This figure is doubled every 5 to 10 years and for individuals over the age of 85, the prevalence of VaD surpasses that of AD. In Australia, there were around 245,400 dementia patients (~37,000 VaD patients) in 2009 and this figure is estimated to reach 1.13 million (~170,000 VaD patients) by 2050. 4 In Asia and some developing countries, the prevalence of VaD is even higher, equaling or exceeding that of AD. 2 VaD significantly impacts on life quality of patients and imposes a huge financial burden on the community and health care system. The total cost of dementia (including VaD) to the Australian health system was estimated at $6.6 billion in 2002, representing 1% GDP and it may exceed 3% of GDP by 2050. 5 ' Ageing well, ageing productively' is a current national research priority and acknowledges the significant burden dementia imposes to the community and health care system.
Cognitive impairment is the primary symptom of VaD. VaD can also cause disturbance of mood and behaviour and reduce quality of life. The pathophysiology of VaD is complex. It incorporates interactions between vascular aetiologies (cerebrovascular disorders and vascular factors), changes in the brain (infarcts, white matter lesions, atrophy) and host factors (age, education). 6 The final common aetiopathogenic pathway usually attributes to a hypoxic, hypoperfusive or occlusive process resulting in ischemic damage in various areas of the brain, with subsequent cognitive and memory function impairment. 3 Currently, effective pharmaceutical interventions for VaD are lacking; standard treatment largely focuses on symptomatic management and prevention of additional brain damage via recognition and control of risk factors such as hypertension and atherosclerosis. 7 Several classes of pharmaceutical agents are used for the symptomatic management of VaD, among which ChE inhibitors and glutamate receptor antagonists are suggested as producing the best clinical outcomes. 3 The most commonly used ChE inhibitors include donepezil, galantamine, rivastigmine and memantine. In two randomised, double-blind, placebo control trials, donepezil demonstrated significant improvement in cognitive function, clinical global impression and activities of daily living in patients with probable or possible mild to moderate VaD. 8 The latest Cochrane review of galantamine in VaD demonstrated contradictory results. One of the two studies included in the review showed that galantamine treatment did not produce significant improvement in ADAS-cog and CIBIC-plus in VaD, while the other study reported a significant improvement in ADAS-cog but not in CIBIC-plus. 9 Rivastigmine is a dual ChE inhibitor, targeting both major forms of ChE -acetylcholinesterase and butyrylcholinesterase. The most recent Cochrane review did not identify any suitable trials to be included in the analysis. Several smaller scale studies however, indicated some beneficial effect of rivastigmine in VaD.
However, these studies suffered from either low patient numbers or did not compare rivastigmine to a placebo. 10 Memantine is a glutamate antagonist and is suggested to produce neuroprotective effects via blocking NMDA-type glutamate receptors. Two recent clinical trials of memantine in mild-to-moderate VaD demonstrated a small but statistically significant improvement in ADAS-cog. However, this result was not supported by a clinical impression of change measured by the CIBIC-Plus. 11 In summary, the existing evidence to support efficacy of pharmaceutical agents in VaD is relatively weak and inconsistent. 12 Moreover, the long-term benefits of these interventions in VaD have not been validated. 12  Ginkgo biloba: Ginkgo biloba leaf extract (ginkgo) has been widely used for management of ageing-related memory disorders. The principal constituents of ginkgo are flavonol glycosides (e.g., quercetin and kaempferol) and terpenoids (e.g. ginkgolide and bilobalide). 14 Data from preclinical studies suggest that ginkgo decreases oxygen radical discharge and proinflammatory functions of macrophages (antioxidant and anti-inflammatory), reduces corticosteroid production (antianxiety), increases glucose uptake and utilization and ATP production. 15 In addition, ginkgo appears to improve blood flow by increasing red blood cell deformability, decreasing red cell aggregation, inducing nitric oxide production and antagonising platelet activating factor receptor. 15 In healthy young adults, ginkgo treatment has been shown to improve speed of processing, working memory, executive function and cognitive function. 16 A recent systematic review revealed that memory enhancement is the most robust acute effect of ginkgo in young adults. 17 In clinical trials with dementia patients (including VaD) however, the effectiveness of ginkgo for enhancing memory and cognitive function remains controversial. Numerous controlled clinical trials demonstrated various levels of improvement in memory loss, concentration, anxiety and other symptoms associated with dementia. 13 For example, a randomized, doubleblind, placebo-controlled trial of 216 participants with AD or VaD showed significant improvements in the attention and memory function in the EGb761 (a standard ginkgo preparation) treated group after 24 weeks treatment. 18 Two more recent studies also demonstrated therapeutic benefits of ginkgo, especially in patients with neuropsychiatric features of dementia. 19,20 In contrast, several clinical trials with greater numbers and longer interventions reported no difference between ginkgo and placebo interventions in dementia treatments, which led to the conclusion in a recent Cochrane systematic review that the existing evidence to support the use of ginkgo remains inconsistent and unconvincing. 21,22 However, a newly published meta-analysis, that considered the baseline risk in the assessment of treatment effect, has shown 6 months of treatment with ginkgo is associated with a significant improvement of cognitive function in dementia patients. 23 It is worth noting that almost all existing clinical trials used the standardised ginkgo preparation, found that ginseng also produces an EEG profile similar to ginkgo, which is consistent with its role as a cognition enhancer. 28 In a series of acute and chronic studies of in humans, the ginseng established robust enhancement of secondary and working memory, which may be related to the ability of ginseng to normalise blood glucose levels. 29,30 Crocus sativus (saffron) is commonly used in traditional Chinese medicine as an antidepressant, antispasmodic, and anticatarrhal. Data from in vivo and in vitro studies demonstrated that saffron possesses neuroprotective properties. Saffron extract has shown to improve learning and memory function in ethanol-induced memory impairment in mice and to ameliorate cerebral ischemia induced oxidative damage in rat hippocampus. 31,32 Crocitin, the principal constituent of saffron and a strong antioxidant, is suggested to be largely responsible for saffron's protective effect on the central nervous system. 31 Multisystem approach of Chinese herbal medicine: Combination therapy underpins the philosophy of Chinese herbal medicine, where patients are generally treated with multi-herbal formulations. There is preliminary evidence that complex chemical mixtures enhance therapeutic efficacy by facilitating synergistic action and/or ameliorating/preventing potential side effects. 33,34 Synergistic effects can occur in many ways, including for example, where constituents from herbal extracts interact with one another to improve their solubility and hence the bioavailability. 34 Furthermore, constituents of complex herbal extracts can affect different targets, which make them ideal therapies for disorders such as VaD, which have multifactorial/multisystem pathophysiological components. 35 Clinical studies in healthy volunteers demonstrate the cognitive effects of a ginkgo-ginseng combination far outweigh those of either extract alone, suggesting the possibilities of synergistic interactions between the extracts. 36,37 Of particular relevance to this study is that this effect was most marked on those tasks which are known to rely on effective cerebral blood supply. Pharmacological studies of SLT: A series of preclinical pharmacokinetic and pharmacodynamic studies were conducted on the three individual herbs and in combination. The data from these experiments demonstrate significant improvements in learning and memory functions, pathogenic biochemical parameters in blood and brain tissue, and antioxidant capacity in various experimental dementia models. [39][40][41][42][43] In an in vivo study, SLT (11,22, and 44 mg/kg per day over 15 days) was administered to dysmnesia models in mice induced by scopolamine, reserpine, chlorderazin, sodium nitrite, and alcohol, respectively. Compared with the control, the middle and high dose treatment of SLT markedly decreased the error numbers and prolonged the latencies of dysmnesia in all active groups. 39 In a chronic cerebral hypoperfusion model induced by bilateral common carotid artery ligation in rats, 8 weeks treatment of SLT (ig) significantly shortened the persistent time for finding the platform in Morris Water Maze. 40 Activity of cholinesterase was also significantly decreased (p<0.05) while the ACh level was markedly increased in the brain tissue (p<0.05). In addition, the activity of superoxide dismutase (SOD) was significantly enhanced (p<0.05). 40 The effects of SLT on ACh were also investigated in an amyloid -protein induced dementia model in mice. 41 38 SLT treatment (16 mg/kg and 8 mg/kg for 7 days) also significantly decreased the platelet aggregation rate and whole blood viscosity in rats. 38 Safety of SLT: Acute toxicity tests on SLT were undertaken in mice. The maximum tolerated dose (MTD) for the formula as whole, ginsenosides, flavone-glycosides and crocins was 1.7g/kg, 4 g/kg, 1.3 g/kg, and 5.0 g/kg, respectively, all of which were significantly higher than the proposed clinical dose (655x, 3422x, 1109x and 21386x respectively). 37 44 Although the baseline characteristics of ADAS-cog differed slightly (statistically insignificant) between the two groups, ANCOVA analysis with the ADAS-cog baseline scores as a covariate showed that the improvement of ADAS-cog scores was significantly greater in the SLT group than those in the placebo group (p<0.005). These results are consistent with the findings from a Single Photon Emission Computed Tomography (SPECT) study of the brain, with a sub-group of patients (n = 7 SLT; n =11 placebo). The SPECT scan results showed that when compared to the placebo, the SLT treatment appeared to increase blood flow in the inferior frontal and anterior temporal lobes, and was more marked on the left. 44 These regions are known to be associated with cognitive, memory, auditory and speech functions of the brain. SLT also significantly reduced the degree of impairment in quality of life caused by VaD as evident by the significant improvement in SF36 scores. 44 Out of 8 domains, significant improvements were observed in the domains of 'role emotion', 'mental health', 'role physical' and 'social functioning' in patients receiving SLT, while significant trends towards improvement were also noted in two other domains -'physical functioning' and 'bodily pain'. No significant differences were found in the placebo group. Two patients out of 64 recruited developed moderate insomnia and headache respectively within the first two weeks of the treatment. Both patients withdrew from the study and were later found to be in the SLT treatment group. In both patients, their symptoms subsided on discontinuation of the treatment. No serious adverse events were observed in this pilot trial.

Study Design
This study will be conducted as a two-arm randomized, double-blind, placebo controlled clinical trial of 65 weeks, including a 52 week intervention and 13 week follow-up.
For a two-arm trial, participants will be randomized after informed consent is obtained, into two parallel treatment groups: The trial will be double-blinded, such that the participants and investigators (including persons responsible for data collection, data management and data analysis) will not be aware of randomization assignments. No pilot study and no run-in period are required for this trial.

Sample
Sample Size Following the release of the Phase II SLT trial results 46 , sample size for this study was recalculated as the two studies used very similar participant cohorts and study design. In particular, the Phase II study provided useful data for VADAS-cog, one of the primary outcomes for the current study. Sample size was calculated using the Phase II trial outcome data for the two primary measures (VADAS-Cog and ADCS-ADLs). Based on their VADAS-Cog data 46 , we expect the minimum between-group endpoint to be 3 or more units (with a standard deviation of 6.56) for a clinically meaningful change in cognition. Using a one-sided independent samples t-test for the purpose of calculating sample size, a total of 166 participants are required to detect this difference with 90% power at the 0.05 significance level. For the ADCS-ADLs, we anticipate the minimum between-group endpoint to be 3 or more units (with a standard deviation of 5.31) for a clinically meaningful change in daily functioning. Using a one-sided independent samples t-test for the purpose of calculating sample size with this measure, a total of 110 participants are required to detect this difference with 90% power at the 0.05 significance level.
Allowing for a total non-compliance/withdrawal rate of 30%, 238 participants will be recruited into the trial across all centres to ensure 166 participants in the final analyses.
For the MRI scanning sub study, to calculate the number of participants required repeated measures analysis of variance was used to examine the power of this study comprising 50 samples with two matched groups measured at two time points. Between factor repeated measures analysis was used to compute the power using the software G*power. 47 Assuming a medium effect size of 0.25, between-measures correlation of 0.5 at 5% level of significance the power was found to be 52%. However accounting for multiple hypotheses tests within the project the power may be reduced significantly. All participants who agree to participate in the main study will be asked if they would like to undergo MRI scanning until 50 participants are recruited. Although it is not possible to ensure equal numbers of treated and placebo participants undergo MRI scanning, that participants will be recruited into the main study in blocks of 6, each of which contain an equal number of treatment and placebo groups, it is likely that the number of treated and placebo participants in the MRI group will be similar.

Participant Characteristics
To achieve the aim of this study, it is desirable that the participant group is relatively homogenous with regard to health profile and disease risk factor presentation to ensure internal validity of the results. However, a broad representation of Australian adults according to demographic and social factors will be sought to improve generalisability of the study findings for the community. The total number of participants with AD+CVD should not exceed a third of the sample size. Participants of each gender, a wide range of ages, ethnic and social backgrounds will be represented in this study.

Inclusion Criteria
To participate in this study, participants must be: • An MMSE score between 10 -24 for the diagnosis of mild to moderate dementia; • Absence of severe depression (Geriatric Depression Scale 15-item version, total score ≤ 11); • Stable or controlled by optimal medication over a minimum of 6 months if on cholinesterase inhibitors and 3 months for (if present) hypertension, diabetes, cardiac disease or stroke, or if on hypnotics and sedatives, stabilised for more than 3 months prior to inclusion in the study; • Agreement to take part in the study as evidenced by a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative if the subject is unable to provide consent), has been informed of all pertinent aspects of the study; • Participants must also be accompanied by a study partner/carer, and this person must be able to assist the participant comply with the study protocol. This requires the study partner/carer to be in contact with the participant at least 2 days per week; • If female, has no intention to become pregnant during the study.
* Rule waiver: a participant aged over 85 years may still be eligible for enrolment if he/she fulfils the following two conditions: (1) the participant meets all inclusion and exclusion criteria of the study; (2) participant's health status is likely to allow for successful completion of the 15 The participant may be considered suitable for this study if his/her frailty score is less or equal to 5 (mildly frail). In such a scenario, a rule waiver will be completed before enrolment.

Exclusion Criteria
Participants will be excluded from the trial if they: • Have other types of dementia and/or severe form of delirium, depression, schizophrenia, acute illness or poorly controlled chronic diseases; • Receive administration of the ingredients in the SLT formula (ginseng, ginkgo and saffron); • Have a history of severe forms of peptic ulcers, diabetes with complications, pulmonary disorders, renal and/or hepatic disorders; • Abnormal pathology test results: Cr > 1.5 times upper limit of normal (ULN); Alt, AST or ALP > 2 times ULN; PT > 3 second more than ULN; APTT > 10 seconds more than ULN; Plt < 100x10 9 /L; • Have a stroke in the 3 months before screening; • Have severe dysphasia, mental retardation and/or life expectancy < 6 months; • Are allergic to more than 2 medications or at least 1 ingredient of SLT; • Are participating in another clinical trial; • Are pregnant or lactating.

Additional Exclusion Criteria -MRI Sub-study
• Allergy to Gadolinium contrast medium • Pacemaker implanted; • Have any wires, clips, or other metal implanted; • Have a cochlear implant.

Discontinuation of Participants from Treatment or Assessment
Should any of the above exclusion criteria present after enrolment of the study, the Investigator will be required to immediately contact the Chief Investigator to determine the next appropriate course of action.
Participants who enter the trial, finish their baseline examination, are allocated to randomised treatment and begin taking the blinded medication will be counted as withdrawal cases if, during the study if they: • Become pregnant; • Withdraw informed consent. Participants are free to discontinue their participation in the trial at any time, without prejudice to further treatment; • Become lost to follow-up during the 52-week trial period; • Demonstrate significant protocol non-compliance as determined by the investigator; or • The Investigator considers that it is not in their interest to continue the study.
The study may be discontinued at any time by the sponsor or the Coordinating Chief Investigator on the basis of new information regarding safety or efficacy. Additionally, the study may be terminated if progress is unsatisfactory. Withdrawn/discontinued participants will not be replaced.

Procedures for discontinuation
In case of premature termination or suspension of the trial, the coordinating chief investigator must inform the trial participants and ensure appropriate follow up and therapy. In addition, the regulatory authorities and ethics committee must be informed.
Participants may withdraw/discontinue from the study at will at any time without explanation.
The participant may also be withdrawn at the discretion of the Investigator due to a safety concern or if judged non-compliant with trial procedures. Participants that withdraw/discontinue from the study will be asked to attend the end of treatment visit (Visit 8, Week 52) to monitor their safety, with a window period of up to 14 days of their withdrawal. The reason for withdrawal and date of withdrawal must be documented in the participant's source data file and electronic Case Report Form (CRF). All AEs and SAEs must be followed until resolution or stabilisation unless, in the Investigator's opinion, the condition is unlikely to resolve.

Concomitant Treatment
Participants may take routinely prescribed medications provided the relevant condition has been stable or controlled by optimal medication for more than 3 months except those drugs prohibited by the Exclusion Criteria. For other medications (including herbal medicine and nutritional supplements), which may have cognitive effects (e.g., cholinesterase inhibitors, beta blockers, angiotensin receptor blockers), the doses should be stable for at least 6 months for ChE inhibitors and 3 months for all other medications prior to the commencement of the trial and remain stable for the duration of the study. The details of all medical treatments and health management plans will be recorded as part of the screening process and then, following enrolment, during every follow-up visit. Notification of a person's enrolment in the trial and the implications for management will be communicated, with their consent, to their General Practitioner. It is anticipated that the presence or effect of any existing treatment confounders or effect modifiers will be equally distributed between groups due to the randomisation process.

Recruitment Protocol
Recruitment strategies to be used in the Australian sites will include: • All clinicians involved in this trial and their associated hospitals, clinics and networks  Resources required for the recruitment phase of the trial include advertising materials, Health Practitioners Information Packages (information sheets for practitioners, information sheets for administration staff, information sheets and contact cards for potential participants). Participants may also be directly mailed information about the trial. Participants can take as much time as is required to consider their participation.

Screening Appointment Protocol
Based on our team's previous experience with recruitment rates for the VaD pilot trial, it is anticipated that 238 participants can be recruited over a 24 month period. The participants will be assessed and classified according to the NINDS-AIREN or NINCDS-ADRDA diagnostic criteria. 48 Mini-mental Status Examination (MMSE) will also be recorded to distinguish types and severity of dementia. A sub-set of 50 participants will undergo Magnetic Resonance Imaging (MRI) scans. Other assessments will include: history and examination, blood tests for reversible dementia, Computer Tomography (CT) scans, and neuropsychological assessment if deemed necessary.

Randomisation and Allocation Concealment Protocol
Randomisation will be conducted external to the primary research team (investigators listed at the start of this document) by a research officer of the National Institute of Complementary Medicine (NICM). This person will be responsible for producing computer generated randomisation treatment sequences which randomly associate a randomisation number with either active or placebo treatment. NICM's Clinical Trials Manager and Strategic Operations Manager are responsible for securely storing the randomisation allocation in a restricted access electronic file.
Randomisation numbers will be allocated in permuted blocks of 6 randomisation numbers starting from 001 to 238 with each block containing 3 active and 3 placebo assigned randomisation numbers. Sites will allocate the randomisation numbers in order of number sequence starting with the lowest number in each block and using all numbers in a block of 6 before starting with the next block of numbers. As soon as the randomisation number is assigned, it will be recorded on the screening log, in the participant source data file and electronic Case Report Form (eCRF). Details of any participants randomised out of sequence will be notified immediately to the Coordinating chief investigator. 3D T1-weighted contiguous coronal sections through whole brain (T1-TFE sequence and 3D acquisition) with voxel size 1 x 1 x 1 mm3; 3D T2-weighted FLAIR contiguous axial slices whole brain with voxel size 1 x 1 x 1 mm3. Then we will perform susceptibility weighted imaging (SWI) for examining cerebral microbleeds. High directional (61-gradient directions) diffusion weighted imaging (DWI) will then follow. We will then carry out angiogram (MRA) scan before taking gd-perfusion scan which is for generating cerebral blood flow and volumes.
We will then do a post-gadolinium enhancement volumetric T1-weighted (this has better grey/white matter contrast than the pre-gd T1-weighted). We have all these T1 and T2 volumetrics (including pre-and post-gd T1s) for an accurate estimation of brain volumetric changes in 12 months. Images will be de-identified, and then transferred to a secure workstation at Centre for Healthy Brain Ageing (CHeBA), UNSW. This protocol will remain the same for the 12-month follow-up scans.

Treatment Description
Shineway Pharmaceutical Co. Ltd. will be responsible for manufacture and container preparation of the two trial intervention agents. The preparations will be manufactured in China in accordance with Australian TGA (Therapeutic Goods Administration) GMP requirements and regulations.

GROUP 2
Placebo capsules will be created by the same manufacturer (Shineway Pharmaceuticals) to have similar colour, taste, texture and weight and will have no constituents which provide therapeutic effects. Participants in Group 2 will take 2 placebo capsules, twice daily for 52 weeks.

Medication Container Labelling Instructions
Each capsule container must state: • Name of sponsor • Pharmaceutical dosage form • Batch/code number to identify contents and packaging operation (may be encoded for blinding purposes) • Directions for use -take orally 2 capsules in the morning and 2 capsules in the evening with meals • Statement "for clinical trial use only" • A trial reference code • Storage conditions • Use-by or expiry date • Statement "keep out of reach of children" And any other items required to be consistent with TG048 (Therapeutic Goods Order TG048)

Clinical Laboratory Parameters and Abnormal Laboratory Test Results
For participants recruited in the Australian centres, tests will be performed by a certified pathology laboratory. Hard copies of all results will be provided to the investigator and transferred electronically to the clinical database.
The following laboratory tests will be performed at The results of all laboratory tests required by the protocol will be recorded in the participant's source data file and in the subject's CRF. All clinically important abnormal laboratory tests occurring during the study will be repeated at appropriate intervals until they return either to the subject's baseline (i.e. the level recorded at Screening) or to a level deemed acceptable by the investigator and the clinical monitor (or his/her designated representative), or until a diagnosis that explains them is made.

Treatment Protocol
An investigator's brochure will be provided to guide all clinical trial staff in protocol details.
Participants will take two capsules of active or placebo medications, orally, twice per day for 52 weeks. Medications will be dispensed at baseline and week 13, 26 and 39 visits. Participants will attend clinic visits at baseline (week 0), and at 4, 13, 26, 39 and 52 weeks for progress and/or adverse event reporting with their sites principal investigator and to collect the next stage supply of medication. Participants and investigating staff will be blinded to treatment allocation until the end of the trial when the data analyses are completed, and the coding is unlocked.
Assessments conducted between weeks -2 (screening) and 0 (baseline) will become the baseline assessments for the study. During the course of the study, assessments will be conducted at weeks 2 (via phone), 4, 13, 26, 39, 52 and 65 (follow-up) weeks after the commencement of treatment (See Table 1). Follow-up assessment questionnaires (65 weeks) will be completed after the treatment period and any adverse events will be closely monitored and reported. All participants will receive 12-months trial medication at the end of the 65-week follow-up period based on compassionate grounds as the product has not yet been made available for purchase in Australia as was anticipated. Provision of the complementary medication will be subject to the principal investigator's judgement and approval by the coordinating chief investigator.
Participant's general practitioner and usual specialist (if relevant) will be informed of the participant's medication prescription and safety will be closely monitored during this period via telephone calls every three months, and requesting participants to continue to keep their adverse event diary. Participants will also be asked to undergo identical pathology tests that have been conducted throughout the trial.
Medication containers will be labelled according to the randomisation schedule at an external location and transferred to all participating centres where they will be kept in a secure storage room and maintained below 30 degrees Celsius. At each appointment, an allocation of medication will be dispensed to participants by hospital pharmacists/research personnel according to the pre-coded container labelling. Participants will be required to return the original containers and any unused medication for monitoring. Any unused medication will then be destroyed locally with approval of the coordinating chief investigator. All delivered and dispensed, unused and returned quantities will be recorded in a medication log. Standardised protocol: 3D T1-weighted contiguous coronal sections through whole brain (T1-TFE sequence and 3D acquisition) with voxel size 1 x 1 x 1 mm3; 3D T2-weighted FLAIR contiguous axial slices whole brain with voxel size 1 x 1 x 1 mm3. Then we will perform susceptibility weighted imaging (SWI) for examining cerebral microbleeds. High directional (61-gradient directions) diffusion weighted imaging (DWI) will then follow. We will then carry out angiogram (MRA) scan before taking gadolinium-perfusion scan which is for generating cerebral blood flow and volumes. We will then do a post-gadolinium enhancement volumetric T1-weighted (this has better grey/white matter contrast than the pre-gd T1-weighted). We have all these T1 and T2 volumetrics (including pre-and post-gd T1s) for an accurate estimation of brain volumetric changes in 12 months. Images will be de-identified, and then transferred to a secure workstation at Centre for Healthy Brain Ageing (CHeBA), UNSW. This protocol will remain the same for 12-months follow-up scans.

Study Procedures: Schedule of Assessments
In response to the COVID-19 outbreak in Australia, study procedures have been amended to protect the safety and wellbeing of participants, their caregivers as well as the research team, and to minimise the impact of the outbreak on the SLT001 trial. Recruitment is to be paused until the trial centre's public health directive and the relevant governance body allow for recruitment to resume. All COVID-19-related strategies are detailed in Appendix 4 of this document. Once the COVID-19 outbreak ceases as per the Australian government's directive, Appendix 4 will cease to be used.

Screening Visit (Week -2 to 0)
Participants eligible for study recruitment, and their study partner/carer, will have the nature, purpose, and risks of the study explained to them by the investigator. Participants (or person responsible), and their study partner/carer, agreeing to participate in the study will sign the informed consent documents. A unique subject screening number will be issued at the time of consent. The screening visit should occur within 2 weeks prior to randomisation (week 0).
Procedures will be performed in the following order: • Informed Consent • Medical history, prior and concurrent medications, and demographics will be documented.
• Body weight and height will be measured.

Baseline visit (Week 0)
Participants who meet all of the inclusion and none of the exclusion criteria will be scheduled to return to the site for their Baseline visit. At Baseline, the following will be performed: • Check of inclusion and exclusion criteria.
• Check concomitant medications and procedures and note any changes in the CRF.

Week 4 Visit
• Check concomitant medications and procedures and note any changes in the CRF.

MRI Scanning Procedures
MRI scans will be performed in 50 VaD or AD + CVD participants in accordance with a standardised scanning protocol. Each MRI session will take 60 minutes. MRI acquisitions will be performed in the following sequential order: a) volumetric (3D) T1-weighted (7 minutes); b) volumetric T2-weighted (3 minutes); c) volumetric Fluid-attenuated inversion recovery (FLAIR) (3 minutes) and they all have a spatial resolution of 1×1×1 mm 3 . Then the following will be carried out: d) susceptibility weighted imaging (SWI) (7 minutes), diffusion weighted imaging (DWI, 61 gradients; 15 minutes), Gadolinium contrast enhanced perfusion (Gd perfusion) (2 minutes); following this we will perform a post Gd volumetric T1-weighted scan (7 minutes).

Drug Accountability
On an ongoing basis all study drugs will be reconciled against delivery, use and returned medication documents. Study drugs which are not used may be destroyed in a suitable facility locally after drug accountability has been completed and with confirmation from the coordinating chief investigator. To be compliant with the treatment protocol study, drug dosing must have a compliance rate of at least 70% over the 52-week study period. Treatment compliance will be calculated by dividing the actual number of capsules taken with expected number of capsules to be taken for the treatment period and multiplying by 100. Self-reported measures of compliance will involve asking participants and their study partner/carer to complete a diary between visits. The researchers will also ask about their adherence to the prescribed treatment regime at the week 4, 13, 26, 39 and 52 visits.

Data Management Protocol
The following source data records will be utilised: • Participant recruitment log • Participant case record forms for screening and data collection. These records will be dated and signed for correct coding, completeness, accuracy and legibility by the chief investigators.
• Adverse event report form Ethics approval will be sought from Human Research Ethics Committees (HREC) for all participating research institutions. The study and investigators will be accountable to these committees by way of ongoing update reports and by providing full access to source data documents.

Ethical guidelines
The trial details will also be submitted to the TGA via CTN (Clinical Trial Notification) arrangements, which will include submission of notification fee and documents of ethical (HREC), sponsor, principal investigators and trial site approval.

Safety and tolerability of interventions
Acute toxicity tests on SLT were undertaken in mice. The maximum tolerated dose (MTD) for the formula as whole, ginsenosides, flavone-glycosides and crocins was 1.7 g/kg, 4 g/kg, 1.3g/kg and 5.0 g/kg, respectively, all of which are significantly higher than the proposed clinical dose (655x, 3422x, 1109x and 20486x respectively). 38 A long term toxicity study was also conducted in dogs. The MTD of SLT is 200 mg/kg, which is 70 times higher than the clinical dose. 37 In an in vitro study, the inhibitory capacity of SLT was evaluated on 5 cytochrome P450 isoenzymes recommended by the US FDA for drug interactions studies. The median inhibitory concentration (IC50) values for CYP1A2, CYP2B6, CYP2D6, CYP2E1 and CYP3A4 were 50-140-fold higher than those potentially achievable by the therapeutic doses. This indicates that SLT treatment is unlikely to cause significant herb-drug interactions. 52 Information about adverse events will be collected by means of a standard question at each visit: Practitioner or other health professionals and co-ordinate emergency medical attention as is appropriate and required. Only in the event of discontinuation in the trial will the randomisation assignment for that participant be made known. If an adverse event is present when the clinical trial is terminated, its course will be followed until the event resolves or the investigator deems it to be unrelated to the trial and appropriate case management is organised.
The definitions for adverse events are presented in Appendix 2. As with most herbal medicines, some mild adverse events might be experienced by some participants. Chinese medicine theory suggests such events may be part of the detoxification and body balancing process, although no evidence can confirm this. Examples of mild adverse events which might be encountered in this study are herbal sensitivity or intolerance symptoms of sore throat, skin rash, vomiting, nausea, asthma, headache, dry mouth, dizziness and insomnia. Moderate to major adverse events might involve impairment of liver and kidney function, abnormal clinical findings of nonphysiological variance or other biochemistry abnormalities. Although serious adverse events (SAEs) are not anticipated for this trial, SAE procedures will be followed in these circumstances.
All adverse events will be recorded as part of trial records or submitted as required to Human

Implications for Participants
Each participant will be required to contribute time to visit the allocated trial centre on eight occasions over a 65-week period.
• Screening consultation • Baseline consultation Subsequent visits for review and medication collection will be briefer. On five occasions (not at 0 and 65-week review), the participants will be required to have a blood sample taken, which may involve brief discomfort but poses no significant health risks. Participants will need to refrain from caffeine and smoking on the morning before blood testing and avoid alcohol and exercise for 24 hours prior to testing. Participants will be reimbursed up to $30 for travel expenses and/or the time spent at each visit. In accordance with the above-mentioned ethical guidelines, a placebo will be utilised in this trial because there is no currently effective alternative medication for treatment of VaD. In addition, participants will continue to take their current prescribed medication.
A subset of 50 participants will undergo MRI scans. MRI scanning does not cause any pain, and the magnetic fields are not known to produce tissue damage of any kind. Some participants may experience discomfort when in an enclosed space or may find the noise of the scanner during testing loud. Earplugs will be provided to prevent problems with noise and participants are able to communication with the technician throughout the procedure. These participants will also be reimbursed for their travel expenses to the MRI centre.
Participants will be insured for their involvement in clinical research through Western Sydney University.

Informed Consent
The protocol of informed consent will be conducted according to guidelines and appropriate national regulations outlined in Section 4.1. Although colleagues may introduce the project to potential participants, the principal investigators must provide written information and verbally discuss the trial with each person.
Informed consent will involve detailed provision at the appropriate level of comprehension for each person, about the purpose, methods, demands, risks, inconveniences, discomforts, benefits and possible outcomes of the research. Each person must exercise voluntary choice to participate, without coercion or inducement and recognise their choice will not impact on their relationships with the research team or their ongoing health management, and be informed that they are free to withdraw from the trial at any time.
The principal investigator will determine the participant's capacity to consent at the screening visit via a discussion of the trial process, and their understanding of it. Both written and verbal explanations of the trial process will be given. For individuals unable to provide personally signed and dated informed consent, guardians/carers of participants with cognitive impairment will be approached to provide consent on the participant's behalf. The person responsible for a participant must meet the legislation and guardianship regulation requirements applicable to the State or Territory in which the trial is being conducted. The person responsible will also be given written and verbal explanations of the trial process and asked to provide written informed consent.
During the screening visit, the investigator must advise the participant and their carer of the possibility that the participant's capacity to consent or participate in research may vary or be lost entirely. This matter will be discussed so the researchers can determine what course of action is to be taken at such times, and whether a person responsible is to be appointed to provide consent on the participant's behalf. It is important that the investigators agree to comply with the participant's wishes; unless these circumstances would prevent the investigator acting in the participant's best interest. The capacity to consent must also be considered at the end of the study, where the participant is due to complete the full 65-week study and is seeking to continue with the post-trial intervention. The principal investigator will determine whether it is safe for the participant to be administered this medication, and whether they have the capacity to consent to the process. In cases where the participant cannot provide consent, the person responsible will be contacted to discuss the nature of this post-trial intervention and provided with the option to consent for this medication on the participant's behalf.
The participant (or person responsible where required), study partner/carer, and the principal investigator will sign two informed consent forms: one for the investigator and one for the participant to keep, in addition to their information sheet. The consent form will state the name and contact details for the principal investigator and study co-ordinators for each recruitment site, who are to be available 24 hours a day, if they have questions or concerns.
It is not envisaged that culturally sensitive issues other than those potentially encountered in the day-to-day running of a clinic would present. All personnel involved in the trial are experienced with conducting clinical practice and clinical research such that cultural needs and beliefs are recognised. If the consenting individual is unable to read the information provided, an impartial witness will be asked to observe the verbal discourse of the trial and witness the signing of the consent form.

Anonymity/ confidentiality/ privacy
In accordance with ethical guidelines, the anonymity, confidentiality and privacy of participants will be protected.
The electronic clinical trial management data system and all electronic data will be password protected. Hardcopy source data records will be kept in a locked cabinet in the office of the principal investigator at each recruitment site during data collection and at completion of the study. Western Sydney University will keep source or certified copies and electronic data for an indefinite period of time.
All publication material will refer to general trial results as aggregate data and no individual participant names or identifying information will be released.
Participants are welcome to view their personal data at any time during the trial.

Outcome Measures
The outcome measurements to be employed in this study are: • Neuropsychiatric Inventory-Clinician rating scale (NPI-C) is a revised version of the Neuropsychiatric Inventory (NPI). The latter is a popular assessment tool for neuropsychiatric symptoms based on a structured interview with a caregiver and comprises 10 neuropsychiatric domains including delusions, hallucinations, depression/dysphoria, anxiety, agitation/aggression, euphoria, dis-inhibition, irritability/lability, apathy, aberrant motor activity and night-time behaviour disturbances. 64 The NPI-C includes additional items, and a clinician-rating methodology and has demonstrated inter-rater reliability and convergent validity in dementia participants.

Primary
• MRI Neuroimaging Assessment: Neuroimaging MRI has increasingly been used in the study of healthy and impaired human cognitive functions associated with neurodegenerative disorders. A significant correlation has been shown between MRI activity and ADAS-cog performance in patients with early Alzheimer's disease. 63 Participants who agree to undergo MRI scanning will be asked to attend two MRI visits to investigate brain changes pre-and post-treatment/placebo (i.e. baseline and 12 months). Each test lasts approximately one hour.
The following outcome measures will be assessed in the study: -A) volumetric changes of both treatment and placebo groups in 12 months by using 3D T1-and T2-weighted MRI scans (including pre-and post-Gd T1 scans). Both T1-weighted and T2-weighted scans will be used as inputs for a multiple-channel segmentation algorithm for an increased accuracy of the computation. Post-Gd T1weighted scans have better grey/white matter contrast and using both scans acquired in the same session will further improve the robustness and accuracy of volumetric estimation.
-B) Changes of white matter lesions by examining the volumetric changes of white matter hyperintensity (WMH) by using our own WMH pipeline. [66][67] -C) Cerebral microbleeds and progress using SWI.
-D) Detailed white matter mapping and change of network properties using DWI scans and diffusion tensor imaging (DTI) analysis using DWI scans will be conducted.
-E) Accurate cerebral blood flow (CBF) and volume (CBV) will be calculated using Gd perfusion scans and to investigate changes of CBF/CBV of treatment and placebo participants. CBF measures how quickly is blood flowing through tissue, in units of mL/100g/min and CBV is the concentration of blood in a tissue, classically measured in units of mL/100g. Perfusion weighted Imaging Tools 69 will be performed to process Gd perfusion scans.
Analysis: Seven grey matter volumetrics will be taken into consideration in the 2 time-point data analyses, i.e. total brain grey matter volume, volumes of 4 cortical lobes, hippocampal volume and total subcortical volume. Three WMH measures will be included, i.e. total brain WMH, periventricular WMH and deep WMH volumes. One cerebral microbleeds measure, i.e.
the count of microbleeds seen in the brain will be included. Further examination of 10 Gd perfusion variables, including 5 CBF (and CBV), i.e. CBF (and CBV) measures of 4 lobes and CBF (CBV) of hippocampus will be conducted.

Safety Measures
• Liver and renal function, and routine haematological and coagulation (PT, APPT and fibrinogen) tests will be conducted at baseline, 4, 13, 26, 39 and 52 weeks after the commencement of the treatment.
• All adverse events will be recorded at each visit, including those suspected to be related to the treatment (such as headache, dizziness, vomiting, allergy, etc) and any worsening of symptoms will be closely monitored. An assessment of the relationship between the adverse events or abnormal test results and the treatment will be made by the chief investigators and Compliance, success of blinding X X X X

Safety analyses
There will be no interim analyses with the exception of monitoring safety variables. The frequency, type and probable association of adverse events will be tallied by de-identified treatment group every 3 months for review by the study team. If there is any significant safety issue identified an additional DMC meeting will be called.

Preliminary analyses and data cleaning
At completion of data collection, all variables and all logical pairs of variables will be subject to descriptive analyses using graphs, frequency counts and summary statistics. This will allow a) identification of unusual or unexpected results for data checking and b) familiarisation with the distributions and associations within the data set. Outcome variables which have severely nonsymmetric distributions will be either transformed or categorised.
At the completion of data checking and correction, the data set will be locked for analysis.

Checking for homogeneity of study centres
As this is a multi-centre study, early analyses will address the question of whether or not there is heterogeneity between centres. Linear models will be fitted to each outcome measure in turn, with centre and centre by treatment added as fixed effects. Any statistically significant differences will be documented and explored further for potential confounding with demographic or medical history factors. If variation between centres cannot be explained (or is shown to be related to differences in study methods), the primary analysis will continue as planned, but will be followed by sensitivity analyses which will either stratify by or exclude the outlier site(s) (depending on the sample size of the site(s) involved).

Demographic and baseline characteristics
The demographic and medical characteristics of participants in each treatment group will be summarised using percentages or means and standard deviations. Pearson's Chi-square and independent samples t-tests will be used to check for any statistically significant differences between groups. Results will be documented as p-values and, where necessary, addressed within the interpretation of study results.

Missing data and protocol violations
In the case of death, all measurements prior to death will be included in the analysis but all after death will be set to missing. To address withdrawals, loss to follow-up or non-compliance with the study analyses will be conducted on both an intention to treat (ITT) and per protocol (PP) basis. Withdrawing and non-compliant participants shall be encouraged to continue with data collection even if stopping treatment. Where data items are missing the last value carried forward method to replace missing data in the ITT analysis will be used. Participants who have significant deviations from the protocol will be removed from the PP analysis after the completion of the ITT analysis. Such significant deviations from the protocol will be determined and documented by the study clinician during the course of the study. Any deviation from randomisation, missing data and withdrawals will be fully reported for this purpose.

Primary efficacy analysis
The primary analysis will be linear mixed models through which we will test for differences between treatment groups on each outcome over time, with adjustment for random variation between treatment centres, with and without adjustment for other potentially important predicts (e.g. compliance, age, gender, severity of VaD). Non-linear changes over time will be tested by a) fitting time as categorical variable and b) testing for quadratic and cubic effects. Results will be reported as regression coefficients (or odds ratios if categorical) and associated 95% confidence intervals.

Subgroup analyses
Secondary analyses will be a repeat of the above stratified by disease type and, if necessary, with stratification by research centre.
Data will be analysed using SAS and/or SPSS software.

SLT001 Trial Contingency Measures
In response to the COVID-19 outbreak in Australia, study procedures have been amended to protect the safety and wellbeing of participants, their caregivers as well as the research team, and to minimise the impact of the outbreak on the SLT001 trial. Recruitment is to be paused until the trial centre's public health directive and their governance body allow for recruitment to resume. All active participants and research staff will be managed to prioritise their safety, and these strategies are detailed in this appendix. These visits can be conducted at the trial centre or nominated community centre, through a home visit, or remotely as per Items 2.1-2.5

SLT001 Trial Contingency Measures for New Participants
• Research personnel must screen for COVID-19 symptoms and refer any suspicious case to qualified facilities for further investigation as per Item 2.3 • COVID-19 safety protection measures must be taken with any face-to-face visits

All Centres
Items to follow up: vital signs, adverse events and safety pathology tests.
Centres will need to assess their current policies and procedures to determine appropriate action for these visits.
Researchers to obtain verbal consent to a home visit, or to collect this information over the phone, and record this in the source visit notes.
For face-to-face visits: the assessors, participant and caregiver will thoroughly wash their hands and/or use hand sanitizer prior to and following a face-to-face visit. Masks and/or gloves to be used in line with local health advice. Centres will need to ensure PPE supplies are readily accessible if conducting face-to-face visits. Face-to-face on-site Part of the testing including VaDAS-cog, Exit-25, CLOX, CIBIS/CIBIC plus will be conducted as per Item 3.1.
Part of the testing including ADCS-ADL, DEMQOL, DEMQOL-Carer and NPI can be conducted remotely (i.e., over the phone) to reduce face-to-face contact time as per Item 3.2

All Centres
Centres will need to assess their current policies and procedures to determine appropriate action for these visits.
Researchers to obtain verbal consent to collect any data remotely and record this in the source visit notes. For face-to-face visits: the assessors, participant and caregiver will thoroughly wash their hands and/or use hand sanitizer prior to and following a face-to-face visit. Masks and/or gloves to be used in line with local health advice. Centres will need to ensure PPE supplies are readily accessible if conducting face-to-face visits.
If unable to collect data, record as Not Done and explain why in the source notes. These tests may be conducted remotely via phone to reduce face-to-face assessment time of Item 3.1, Options 1, 2, and 3.

All Centres
Researchers to obtain verbal consent to collect any data over the phone and record this in the source visit notes. (1) Centres where no on-site visits are possible: 6month supply of IP to be delivered by a courier service or through a home visit by a study team member, with visit 6 and 7 diaries, and instructions to keep empty packaging/leftover capsules (2) Centres where site visits are still allowed: IP to be collected from pharmacy or delegated personnel All Centres Obtain verbal consent to receive 6month IP supply and record this in source notes.
Centres will organise delivery of IP. (1) Screen all participants over the phone for cold and flu symptoms, recent overseas or interstate travel and any close contact with a confirmed or suspected COVID-19 case in the past 14-days − Participants with these symptoms should be referred to qualified facilities for further investigation − Participants with these symptoms requesting advice should be directed to the Health Direct Line 1800 020 080 or website https://www.healthdirect.gov.au/coronavirus (2) If the participant is diagnosed with a coronavirus infection, trial medication may be suspended until symptoms resolve All Centres (1) Personnel to conduct COVID-19 safety check with every call to a participant and delegated Investigators must review any reports of symptoms; (2) Do not see or assess participant on study instruments, or proceed with pathology test, if symptoms present and cause is being investigated. Delay appointment until they have been cleared.

Safety Pathology Testing
Conducted at hospital/local pathology laboratories If participant passes the COVID-19 checks, participant will be offered to verbally consent to the following two options: (1) Continue to use the current pathology lab for the testing when on-site visit to pathology lab is permitted (2) Home visit of a study team member or a mobile venipuncturist to take blood and deliver to the pathology lab for analysis; infection control procedures will be enacted as per Item 3.1 If the participant declines to take either option, the medical history and previous pathology results of the participant will be assessed by the PI and coordinating CI to determine if this participant can continue in the trial All Centres NICM For Option 1, Pathology slip will be provided to participant; Sponsor to cover the costs of taxi/Uber if needed to avoid public transport.
For Option 2, Sponsor to cover the mobile blood collection services if relevant.
Centres to record verbal consent to remote blood collection in source visit notes. 2) Verbally consenting to being assessed at a nominated community centre; COVID-19 safety check and protection measures must be taken as per Item 3.4

SLT001 Trial Contingency
3) Verbally consenting to receive a home visit from assessors; COVID-19 safety check and protection measures must be taken as per Item 3.4 4) For the sites where both on site and home visits are not feasible, and/or participants are unwilling to attend in person, the possibility of using telehealth or videoconferencing to conduct these assessments will be explored All Centres Centres will need to assess their current policies and procedures to determine appropriate action.
Researchers to obtain verbal consent to collect any data remotely and record this in the source visit notes.
For face-to-face visits: the assessors, participant and caregiver will thoroughly wash their hands and/or use hand sanitizer prior to and following a face-to-face visit. Masks and/or gloves to be used in line with local health advice. Centres will need to ensure PPE supplies are readily accessible if conducting face-to-face visits.
If unable to collect data, record as Not Done and explain why in the source notes.
. If face-to-face visit not feasible, and participant and Investigator proceed with 12 month openlabel supply of SLT medication, researchers must obtain verbal consent to deliver IP with post-trial adverse event diary. This can be done through a courier service, or by a study team member conducting a home visit.

NICM and All Centres
Researchers to obtain verbal consent to have post-trial IP and visit diary delivered, and record this process in source visit notes; NICM will continue the remote monitoring of their safety via regular phone calls.

4.2
Post-trial Safety Pathology Testing Conducted at hospital/local pathology laboratories Laboratory studies will be conducted only if an adverse event is reported in the post-trial period and the Investigator deems it necessary to perform this test; These will be carried out in accordance with Item 3.5.

All Centres
Refer to Item 3.5 for the conduct of Investigator initiated laboratory studies.